I just received the news yesterday from Bill Winter that we have sadly lost Tony Sarko from this world. I would like to express first my sorrow and best wishes to his family and friends, and a message of sympathy from Switzerland to Syracuse. He will be missed.
Tony was a key person in my life, a mentor who stepped in at a key turning point for me as a student, a stepping stone upon which I launched my scientific career, an influence I carry with me in my work and actions today.
As a graduate student in Syracuse I had become frustrated with our approach of correlating experimental properties of polymers with descriptors. We were generating data but did not seem to have an understanding of the phenomena we were studying. At first, I tried mathematical approaches from molecular statistical mechanics, which was helpful in advancing my understanding, but still fell short in being able to simulate mechanisms and study them in detail. I stumbled upon the work of Martin Karplus at Harvard who was using computers to study the structure and dynamics of proteins (which led a couple of years ago to a Nobel Prize, and a first in such computational science) and I was hooked. This seemed to be the way to go – I would now try to use molecular computer simulations to both understand the mechanisms and eventually to predict and design structural properties and outcomes. In the last couple of decades these methods have advanced tremendously and such computational science has become a cornerstone of both academic research and industrial applications. However, back then in my graduate student days, no one around the campus in Syracuse seemed to know anything about such approaches. I started exploring and developing and applying such programs, and spent many lonely but absorbed days programming. However, to defend a dissertation on such a topic, I would need a professor to act as my advisor, but none seemed to exist. I had reached a turning point in my career with a new found passion, but was lost in the system I needed to progress through. But then I went and talked with Tony Sarko and he saved the day for me, and I have not looked back since.
Tony had worked as an experimental scientist at SUNY for many years using x-ray diffraction to study the structure of cellulose. However, the experimental data alone was insufficient to produce a clear result and Tony had hence used molecular models and computers to help solve his problem. He immediately saw the value and potential in my ideas, and also had the relevant experience to become my advisor, and he accepted to do that. I was hence able to start my journey of working on programs for running the simulations, getting them working on supercomputers and programming new graphics workstations of that time to produce pictures and movies to visualise and understand the large amount of data produced. Tony was also hands-on and programmed himself the visualisation of structures and I worked with code to add some new techniques in animation to bring the simulations to life as movies. We shared the excitement of watching such movies together. These days such applications are common, but back then I spent weeks running simulations, carrying tapes across campus and lots of time hand-coding the animations. When the movies were finally on the screen, it was a moment of great excitement to share.
Tony mentored me and always was available to talk about my work and problems, and also helped me to navigate to results, publications and a successful dissertation defence. But it was also a long journey. I had underestimated how challenging the work would be and spent three years programming the simulations and analysing the results. Ideas and ambitions I had also fell short, as I understood there were many years ahead to get to the point where some of the goals could be realised. It was a lonely road at times and sometimes I thought I would never reach an endpoint. Tony however empathised with me, was a shoulder to lean on when I was down, and was always there to encourage me, when all looked impossible. We would have a meeting, he would listen to my troubles, and provide sound advice. I would take the encouragement with me and with renewed energy tackle the next problems. For example, I spent one year parallelising computer code to run on parallel supercomputers of that time, so that I could produce the needed simulation results. A lesson to take is that empathy and encouragement is a key component to scientific and technical work, and I have carried that spirit and value with me throughout my career. It was also the first seed for me to understand the importance of collaboration, a value I very much follow in my activities today. Let’s not forget that empathy is more powerful than technology, but both together can improve the chance of success to achieve a great goal. We need to be there for supporting each other in our work! Thank you Tony for that gift.
Based on the start Tony gave me, I then was able to move on to a National Research Council fellowship with Richard Pastor at the FDA, where we published ground-breaking work on using such computer simulations on the structure and dynamics of membranes in Science. In turn that led to working on problems in recognition and drug design as the first Hitchings-Elion fellow at Oxford, under the mentorship of Graham Richards. I was fulfilling my dreams. I then found the new world of the World Wide Web and did not hesitate to explore a new direction and moved on into the business world. I was able to easily and naturally do that because of that confidence that Tony gave me in exploring the unknown and the challenging. I have tried to follow that example in my mentoring of team members since and today, and to also be open to new mentoring myself, as I take on new responsibilities and challenges in both science and business.
In recent years I have returned to the world of in silico data, analysis and modelling, applying these techniques to the goal of using new safety assessment methods replacing animal testing, and including impact on industry and regulation. This is no longer just an academic exploration. I am more mature in my views today seeing the value of combining experiment, data analysis and modelling, and forming collaborations and partnerships to do that. In a new development, we are currently setting up an experimental lab where we are bringing our in silico solutions into the lab and connecting experiments more closely with analysis and modelling. When I see new advances today such as applying simulations to understanding key interactions such as between nanomaterials and biological systems, I immediately see the value and the promise, but also the challenges. I encourage these developments just like Tony did with me as a student. I try to understand, support and help enable the advance. With going back to the lab more these days, I am completing a personal circle - going back to the experimental world where I started out, understanding the mechanisms and the data and bringing it together with the modelling supporting outcomes and solutions. I wanted to talk to Tony about this recently, but we did not quite get to have our meeting. However, I am sure he would be pleased to see where his support of my early career led and is still leading, and those conversations will somehow still exist and continue.
Thank you again Tony for being there at a critical point in my life, for supporting and working with me, and do rest in peace.
Barry
The theme of the ACS meeting activities in Boston the next few days is one close to our values and current attention with Douglas Connect and our communities and partners: Innovation from Discovery to Application.
I will present on a few of our initiatives on this innovation path at the meeting in Boston and will upload the presentations on the net (including here).
Look forward to interacting in Boston or virtually!
Barry
Monday 17 August
8-10.30, room 103
Session on Workflow Tools & Data Pipelining in Drug Discovery
chaired by Tim Dudgeon and Erin Davis
9.30
Workflows supporting drug discovery against malaria
Barry Hardy, Thomas Exner and Alessandro Contini
The goal of Scientists Against Malaria (SAM) is the discovery of novel anti-malarial compounds. SAM supports virtual drug discovery organizational structures collaborating on target selection and modeling, protein expression and assay development, computational drug design, and screening. A combination of interoperable information systems, ontologies and web services were designed and deployed to manage the data, documents, computational and assay results, activity and toxicology predictions, as well as dashboards to track project progress and to support decision making. Workflows were developed for consensus virtual screening of candidate malarial kinase inhibitors including docking, pharmacophore-based screening and free energy-based molecular simulations. The models were applied to the discovery of active ligands against a novel target with previously unknown structure or ligands. The workflows were extended to include OpenTox model web services to prioritize drug candidates according to their predicted toxicities, supporting a weight of evidence categorization of candidate molecules according to their activity and toxicity profiles.
DOWNLOAD SAM Drug Discovery Presentation Download 150817 SAM ACS
13-18.00, room 103
Session on The Growing Impact of Openness in Chemistry: A Symposium in Honor of JC Bradley
chaired by Andrew Lang and Antony Williams
14.55
OpenTox - an open community and framework supporting predictive toxicology and safety assessment
Barry Hardy
One important goal of OpenTox is to support the development of an Open Standards-based predictive toxicology framework that provides a unified access to toxicological data and models. OpenTox supports the development of tools for the integration of data, for the generation and validation of in silico models for toxic effects, libraries for the
development and integration of modelling algorithms, and scientifically sound validation and reporting routines.
The OpenTox Application Programming Interface (API) is an important open standards development for software development purposes. It provides a specification against which development of global interoperable toxicology resources by the broader community can be carried out. The use of OpenTox API-compliant web services to communicate instructions between linked resources with URI addresses supports the use of a wide variety of commands to carry out operations such as data integration, algorithm use, model building and validation. The OpenTox Framework currently includes, with its APIs, services for compounds, datasets, features, algorithms, models, ontologies, tasks, validation, reporting, investigations, studies, assays, and authentication and authorisation, which may be combined into multiple applications satisfying a variety of different user needs. As OpenTox creates a semantic web for toxicology, it should be an ideal framework for incorporating toxicology data, ontology and modelling developments, thus supporting both a mechanistic framework for toxicology and best practices in statistical analysis and computational modelling.
In this presentation I will review the recent OpenTox-based development of applications including the ToxBank data infrastructure supporting integrated analysis across biochemical, functional and omics datasets supporting the safety assessment goals of the SEURAT-1 program which aims to develop alternatives to animal testing.
Finally, I will provide an overview of the working group activities of the newly formed OpenTox Association which aim to progress the development of open source, data, standards and tools in this area.
DOWNLOAD OpenTox Presentation: Download 150817 OpenTox ACS
Tuesday 18 August
13.30-17.00, waterfront 1A/1B
Session on Current Topics in Chemical Safety Information
chaired by Leah McEwen and Ralph Stuart
15.40
eNanoMapper - A Database and Ontology Framework for Nanomaterials Design and Safety Assessment
Barry Hardy, Egon L. Willighagen, Janna Hastings, Markus Hegi, Lucian Farcal, Nina Jeliazkova, Haralambos Sarimveis
The eNanoMapper EU FP7 project is developing a data management and analysis infrastructure together with ontologies supporting the safety assessment activities of the European nanomaterials research and development community. The project addresses the requirements of safety assessment of nanomaterials by providing databases, analysis tools and ontologies for risk assessment and linking them with existing resources in this area.
The work involves close cooperation with the EC NanoSafety Cluster members and other international organisations such as the EC JRC, and the EU-US NanoEHS cooperation initiative. Their requirements guide the development of tools for experimental design, model building, systems biology, and meta analysis across multiple datasets.
An ontology for nanosafety research is being developed to provide the following features: annotation of nanostructures and relevant biological properties, annotation of experimental model systems (e.g. cell lines), conditions, and protocols, complex search and reasoning capabilities, and the integration of data from existing nanotoxicology sources.
Systematic physicochemical, geometrical, structural, and biological studies of nanomaterials are rare in the public domain and data sharing is only just commencing, given the absence of readily available solutions for that purpose. eNanomapper will address that issue, as the establishment of a universal standardisation schema and infrastructure for nanomaterials safety assessment is a key goal of the project. It will catalyze collaboration, integrated analysis, and discoveries from data organised within a knowledge-based framework. It will support the discovery of nanomaterial properties responsible for toxicity, the identification of toxicity pathways and nano-bio interactions from linked datasets, ontologies, omics data and external data sources.
By interfacing with statistical and data mining tools, eNanoMapper aims to provide scientifically sound guidelines for experimental design as well as computational models for predicting nanotoxicity. These computational models will help to design safe nanomaterials and improve the risk assessment of existing nanoparticles.
This presentation will provide an overview of the progress made in the initial 18 months of the project, including outlines of the initial development releases of the data platform and ontology.
Download eNanoMapper presentation: Download 150813 eNanoMapper ACS Boston
Wednesday 19 August
08.15 - 17.10, room 103
Session on Computational Toxicology: From QSAR Models to Adverse Outcome Pathways
chaired by Mohamed AbdulHameed
Using OpenTox to map toxicity data to AOPS
Barry Hardy
09.20
OpenTox provides a framework where data and model predictions can be retrieved from a federated set of data sources.
In this presentation we will discuss the concept of using relevant information (including its retrieval and organisation from multiple sources) in the development and application of Adverse Outcome Pathways (AOPs).
Analysis and discussion of the information obtained were used in conjunction with a collaborative wiki based approach to AOP development and interpretation.
We discuss the requirements and prospective solutions for the further computational development of AOPs e.g., using data and metadata to semantically annotate AOP nodes, challenge limitations in an AOP or propose new nodes for the AOP.
We will present meta analysis examples from the ToxBank data infrastructure project supporting integrated analysis across biochemical, functional and omics datasets supporting the safety assessment goals of the SEURAT-1 program which aims to develop alternatives to animal testing.
Download OpenTox, ToxBank and AOPS presentation Download 150819 OpenTox AOP 1.2
Following up on the initial OpenTox project which was funded by the EU under FP7, OpenTox has developed as an open standards platform supporting application and infrastructure development in predictive toxicology and safety assessment. The OpenTox Association was founded 27 March this year as an international member-based non-profit association.
The purpose of the Association is to promote the community-based exchange and use of open knowledge, software, methods, tools, data, reference resources, and standards in the scientific activities of predictive toxicology, safety assessment and risk management, including the 3Rs goal of the Reduction, Refinement and Replacement of Animal Testing. Working groups have been formed which working virtually on an ongoing basis to elaborate further the open standards and integrating resources approach developed by the OpenTox community.
The OpenTox Euro 2015 meeting takes place 30 Sept - 2 Oct in Dublin, Ireland. The conference theme is Reproducible High Quality Safety Science on Complex Systems and will include conference sessions on Information Requirements & Standards, Characterisation of Systems, High Content Screening, Metabolism, Modelling Cellular Perturbations & Responses, Linking Parameters & Evidence across Scales, Simulation, Systems Biology and Knowledge Integration Supporting Decision Making.
OpenTox Association Working group meetings will be held on the topics of Application Programming Interfaces, Adverse Outcome Pathways, Data and Metadata Standards and Resource Deployment. The meeting will also include a General Assembly of the Association in addition to hands-on modelling and analysis sessions, poster session and knowledge cafes.
To submit an abstract for the meeting:
(Deadlines: 31 July for speaker program, 31 August for posters)
http://www.opentox.net/submit-abstract-poster-or-chair
Information and updates on the program will be posted at:
http://www.opentox.net/events/opentox-euro-2015
Barry Hardy
President, OpenTox Association
On behalf of the Organising Committee
More information on the OpenTox Association:
http://www.opentox.net/the-opentox-association
We are offering bursary awards for attending the hands-on eCheminfo drug design workshops taking place in Milan (20-24 July) and Toronto (24-28 Aug) this summer.
Candidates should complete the application form by 15 May:
Our close scientific co-workers Roland Grafstrom and Pekka Kohonen, have been awarded the scientific Lush Prize recognising their recent research achievements in advancing alternative testing methods, including with the bioinformatics data analysis work done with us on ToxBank.
Well done Roland and Pekka, and a well deserved honouring too!
More information on the Lush 2014 Prize is located at:
http://www.lushprize.org/2014-prize/2014-prize-winners/
Drug Design in India, Malaria Focus - we are taking the eCheminfo drug design workshop activities we have developed in Oxford in recent years to India in January.
http://barryhardy.blogs.com/cheminfostream/2014/10/drug-design-in-india-malaria-focus.html
On the 13 February 2015 we will hold an InnovationWell workshop at Johns Hopkins, Baltimore.
The goal of the workshop is to discuss experiences, practices and solutions in drug development and translational medicine.
We will discuss case study experiences involving collaboration in drug and biotech discovery and development, obstacles experienced in practice and methods used to overcome barriers, approaches used to data sharing including IP and contractual issues, practices in knowledge management and innovation success.
We will subsequently flush out the real problems and issues involved in current practices in translational medicine, identify the strengths and weaknesses in current approaches being used and explore new strategies that might be of use to address and achieve improved translational success.
The workshop will be facilitated by Frank Hollinger (Sphaera Pharma), Michael Liebman (Strategic Medicine) and Barry Hardy (Douglas Connect).
Further information on the program can be found at
http://www.innovationwell.net/events/innovationwell-2015
I am pleased to announce the program for the OpenTox USA 2015 meeting which will take place 10-12 Feburary at Johns Hopkins, Baltimore.
The goal of the meeting is to discuss and develop important components for driving 21st century approaches to safety assessment forward. We assume that collaboration driven by an open global platform and open standards will be a key success factor. Integrating heterogenous evidence supported by a common knowledge framework and ecosystem of tools and partners will enable practical application, judgements and decisions including industrial application and regulatory acceptance.
The program will involve conference sessions and associated hands-on workshops, poster session and knowledge cafes.
The main themes of the meeting are:
Data Science, facilitated by Barry Hardy (Douglas Connect)
Adverse Outcome Pathways, facilitated by Stephen Edwards (US EPA)
Exposure Modelling, facilitated by Tim Pastoor (Syngenta)
Integrating Evidence and Analysis, Thomas Hartung (Johns Hopkins)
Risk Assessment & Management Applications, Grace Patlewicz (Du Pont)
We are open for submission of abstracts for consideration for the program.
Further information on the program can be found at
http://www.opentox.com/events/opentox-usa-2015
On behalf of the OpenTox Community and the Organising Committee.
I am pleased to inform that we are commencing providing public acccess to the ToxBank Data Warehouse.
Public access to the data warehouse may be requested using the form available at: http://www.toxbank.net/enquiries/request-data-warehouse-access
Users may access protocols or data that have been made available within the ToxBank Data Warehouse.
We also provide a request option to support the incorporation of data.
Tutorials on the use of the ToxBank resources are made available in the ToxBank Library at http://www.toxbank.net/tutorials